Based on the discovery that glucocorticoid-induced loss of bone strength results in part from increased[unreadable] death of osteocytes independent of bone loss, and evidence that cortisol levels as well as local tissue[unreadable] amplification of glucocorticoid action increase with age in both mice and humans, the hypothesis that the[unreadable] disparity between bone strength and mass that occurs with aging is due in part to the adverse skeletal[unreadable] impact of endogenous glucocorticoids will be tested. This enhancement of glucocorticoid effects would[unreadable] result in an increase in the prevalence of osteocyte apoptosis and prolongation of osteoclast lifespan.[unreadable] Glucocorticoid effects on these cells result from nongenotropic mechanisms involving proline-rich tyrosine[unreadable] kinase 2 (Pyk2) activation. The ensuing glucocorticoid-induced osteocyte apoptosis negatively affects bone[unreadable] strength by disrupting canalicular circulation, degrading material properties, allowing accumulation of[unreadable] damaged bone, or all three. To test this hypothesis, in Aim 1, the contrast in vivo between the loss of bone[unreadable] mineral density (BMD) and strength at 8, 16, and 25 months of age in wild-type and transgenic mice[unreadable] overexpressing 113-hydroxysteroid dehydrogenase type 2, an enzyme that inactivates glucocorticoids in a[unreadable] pre-receptor fashion, will be determined. This will be accomplished either under the control of the[unreadable] osteocalcin promoter (thus protecting osteocytes and osteoblasts from glucocorticoid action) or under[unreadable] control of the tartrate-resistant acid phosphatase promoter (thus protecting osteoclasts from glucocorticoid[unreadable] actions). In Aim 2, the role of the focal adhesion-related protein Pyk2 in the opposing effects of[unreadable] glucocorticoids on osteocyte and osteoclast lifespan will be delineated. Specifically, those opposing effects[unreadable] are the induction of osteocyte apoptosis and prevention of osteoclast apoptosis. In Aim 3, the contribution[unreadable] of osteocyte apoptosis to bone strength will be determined by inducing rapid, conditional osteocyte ablation[unreadable] via apoptosis using diphtheria toxin administration and the dentin matrix protein 1 promoter controlling the[unreadable] diphtheria toxin receptor in mice, an otherwise diphtheria toxin-insensitive species. The innovative studies[unreadable] proposed in this project will extend previous work by delineating the contribution of endogenous[unreadable] glucocorticoids to the multifactorial damages that affect the aging skeleton. The importance of this project is[unreadable] amplified by the increasing burden of osteoporosis that will occur with the aging of America. Older people[unreadable] are more sensitive to the adverse skeletal effects of glucocorticoids and this project will provide a detailed[unreadable] investigation of how the glucocorticoids produced by their adrenal glands contribute to fractures in the agjng[unreadable] skeleton.